We have previously demostrated a characteristic change in the action potential pattern for cat ventricular myocardial cells 3-7 days following the induction of chronic pressure overload of the right ventricle. Typically, there is a drop (less negative) in the action potential plateau which return to normal hypertrophy sets in with or without overt heart failure; when failure results, a depression in the resting and action potential is also manifested. We have interpreted the alteration of the action potential as a diminished calcium influx into the myocardial cell during excitation which in turn might reduce cellular stores of calcium thereby attenuating contractility. One of the objectives of this project is to study in depth the relationship between the cardiac action potential and mechanical activity during the events triggered by experimentally induced right ventricular pressure overlaod. A second objective is to evaluate the effects of drugs on the course of these events, particularly the ionophore X-537A which is known to provide a means for increasing intracellular calcium stores. It is of considerable significance that this drug also produces an alteration of cardiac action potential plateau opposite to that which follows pressure overload. A third objective is to evaluate the effects of the cardiotonic ionophores on the myocardial electrophysiological, mechanical and hemodynamic parameters of those cats which ultimately exhibit overt failure. The techniques which will be emloyed to correlate the electrical and mechanical evens induced by pressure overload include microelectrode and isometric recording techniques, potassium induced contracture and voltage clamping on ventricular muscles from normal and sham operated cats during the various response phases following pressure overload produced by chronic pulmonary artery occlusion. We will also examine the subcellular capacity for controlling calcium distribution in mitochondria and sarcoplasmic reticulum isolated from these cat hearts. The comprehensive objective of this project is to explore the etiology of pressure overload induced heart failure and whether the course of events preceding failure may be altered by appropriate drug intervention. Ultimately, it is hoped to gain information which could lead to the pharmacological control of an important class of progressive human cardiomyopathies.